This invention relates to an improved method for the preparation of N-[2-(cyclohexen-1-yl)ethyl]-4-methoxybenzeneacetamide, a useful intermediate in the preparation of dextromethorphan, an antitussive agent employed in cough syrups.
The preparation of dextromethorphan as with many pharmaceutically active compounds requires a plurality of chemical reaction steps and the formation of a number of intermediates. A key intermediate in the preparation of dextromethorphan is N-[2-(cyclohexen-1-yl)ethyl]-4-methoxybenzene acetamide having the structural formula ##STR6## Heretofore there has been one principal commercial method for preparing this intermediate [see U.S. Pat. No. 3,634,429 and Helv. Chem. Acta, 34 1437 (1950)]. This method consists of converting cyclohexylidene cyanoacetic acid to 1-cyclohexenylacetonitrile which is reduced to the corresponding amine using lithium aluminum hydride. The amine derivative is then reacted with 4-methoxyphenyl acetic acid to obtain the desired intermediate (V). Because the use of lithium aluminum hydride is both expensive and hazardous an alternate, commercially attractive method is desirable. It has been found that the desired intermediate (V) can be obtained in good yield by a method which avoids the costly and potentially unsafe lithium aluminum hydride reduction step. The preparation of this intermediate is accomplished according to the following chemical reaction scheme: ##STR7##